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      Pharmacokinetics of Monoclonal Antibodies

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      Author(s): 1 , 1 ,
      Publication date (Electronic):
      Journal: CPT: Pharmacometrics & Systems Pharmacology
      Publisher: John Wiley and Sons Inc.

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          Abstract

          Monoclonal antibodies (mAbs) have developed in the last two decades into the backbone of pharmacotherapeutic interventions in a variety of indications, with currently more than 40 mAbs approved by the US Food and Drug Administration, and several dozens more in clinical development. This tutorial will review major drug disposition processes relevant for mAbs, and will highlight product‐specific and patient‐specific factors that modulate their pharmacokinetic (PK) behavior and need to be considered for successful clinical therapy.

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          Clinical pharmacokinetics of therapeutic monoclonal antibodies.

          Ron J. Keizer, Alwin D. R. Huitema, Jan Schellens … (2010)
          Monoclonal antibodies (mAbs) have been used in the treatment of various diseases for over 20 years and combine high specificity with generally low toxicity. Their pharmacokinetic properties differ markedly from those of non-antibody-type drugs, and these properties can have important clinical implications. mAbs are administered intravenously, intramuscularly or subcutaneously. Oral administration is precluded by the molecular size, hydrophilicity and gastric degradation of mAbs. Distribution into tissue is slow because of the molecular size of mAbs, and volumes of distribution are generally low. mAbs are metabolized to peptides and amino acids in several tissues, by circulating phagocytic cells or by their target antigen-containing cells. Antibodies and endogenous immunoglobulins are protected from degradation by binding to protective receptors (the neonatal Fc-receptor [FcRn]), which explains their long elimination half-lives (up to 4 weeks). Population pharmacokinetic analyses have been applied in assessing covariates in the disposition of mAbs. Both linear and nonlinear elimination have been reported for mAbs, which is probably caused by target-mediated disposition. Possible factors influencing elimination of mAbs include the amount of the target antigen, immune reactions to the antibody and patient demographics. Bodyweight and/or body surface area are generally related to clearance of mAbs, but clinical relevance is often low. Metabolic drug-drug interactions are rare for mAbs. Exposure-response relationships have been described for some mAbs. In conclusion, the parenteral administration, slow tissue distribution and long elimination half-life are the most pronounced clinical pharmacokinetic characteristics of mAbs.
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            Strategies for extended serum half-life of protein therapeutics.

            R E Kontermann (2011)
            With a growing number of protein therapeutics being developed, many of them exhibiting a short plasma half-life, half-life extension strategies find increasing attention by the biotech and pharmaceutical industry. Extension of the half-life can help to reduce the number of applications and to lower doses, thus are beneficial for therapeutic but also economic reasons. Here, a comprehensive overview of currently developed half-life extension strategies is provided including those aiming at increasing the hydrodynamic volume of a protein drug but also those implementing recycling processes mediated by the neonatal Fc receptor. Copyright © 2011 Elsevier Ltd. All rights reserved.
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              CNS Delivery Via Adsorptive Transcytosis

              Françoise Hervé, Nicolae Ghinea, Jean-Michel Scherrmann (2008)
              Adsorptive-mediated transcytosis (AMT) provides a means for brain delivery of medicines across the blood-brain barrier (BBB). The BBB is readily equipped for the AMT process: it provides both the potential for binding and uptake of cationic molecules to the luminal surface of endothelial cells, and then for exocytosis at the abluminal surface. The transcytotic pathways present at the BBB and its morphological and enzymatic properties provide the means for movement of the molecules through the endothelial cytoplasm. AMT-based drug delivery to the brain was performed using cationic proteins and cell-penetrating peptides (CPPs). Protein cationization using either synthetic or natural polyamines is discussed and some examples of diamine/polyamine modified proteins that cross BBB are described. Two main families of CPPs belonging to the Tat-derived peptides and Syn-B vectors have been extensively used in CPP vector-mediated strategies allowing delivery of a large variety of small molecules as well as proteins across cell membranes in vitro and the BBB in vivo. CPP strategy suffers from several limitations such as toxicity and immunogenicity—like the cationization strategy—as well as the instability of peptide vectors in biological media. The review concludes by stressing the need to improve the understanding of AMT mechanisms at BBB and the effectiveness of cationized proteins and CPP-vectorized proteins as neurotherapeutics.
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                Author and article information

                Contributors
                Bernd Meibohm: bmeibohm@uthsc.edu
                Journal
                Journal ID (nlm-ta): CPT Pharmacometrics Syst Pharmacol
                Journal ID (iso-abbrev): CPT Pharmacometrics Syst Pharmacol
                Journal ID (doi): 10.1002/(ISSN)2163-8306
                Journal ID (publisher-id): PSP4
                Title: CPT: Pharmacometrics & Systems Pharmacology
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2163-8306
                Publication date (Electronic): 29 July 2017
                Publication date (Print): September 2017
                Volume: 6
                Issue: 9 ( doiID: 10.1002/psp4.v6.9 )
                Pages: 576-588
                Affiliations
                [ 1 ] Department of Pharmaceutical Sciences College of Pharmacy, University of Tennessee Health Science Center Memphis Tennessee USA
                Author notes
                [*] [* ]Correspondence: B Meibohm ( bmeibohm@ 123456uthsc.edu )
                Article
                Publisher ID: PSP412224
                DOI: 10.1002/psp4.12224
                PMC ID: 5613179
                PubMed ID: 28653357
                SO-VID: 99824df3-efb8-4bcf-ad2b-0acb774b42c1
                Copyright © © 2017 The Authors
                License:

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 31 March 2017
                Date revision received : 19 June 2017
                Date accepted : 20 June 2017
                Page count
                Figures: 5, Tables: 1, Pages: 13, Words: 10837
                Categories
                Subject: Tutorial
                Subject: Tutorial
                Custom metadata
                source-schema-version-number 2.0
                component-id psp412224
                cover-date September 2017
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.0 mode:remove_FC converted:26.09.2017

                Data availability:

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